Preparation of imidazole-2-carboxylic acids

ABSTRACT

4,5-Disubstituted imidazole-2-carboxylic acids are prepared by reacting 4,5-disubstituted imidazoles with carbon dioxide under superatmospheric pressure at from 150° to 300° C. in the presence of a base.

The present invention relates to a novel process for preparing 4,5-disubstituted imidazole-2-carboxylic acids by reacting 4,5-disubstituted imidazoles with carbon dioxide under superatmospheric pressure at from 150° to 300° C. in the presence of a base.

The present invention further relates to novel 4,5-disubstituted imidazole-2-carboxylic acids.

The literature discloses the following ways of preparing benzimidazole-2-carboxylic acids:

condensation of o-phenylenediamine with glycolic acid to give 2-hydroxymethylbenzimidazole and subsequent oxidation with KMnO₄ (A. Bistrzycki, G. Przeworski, Chem. Ber. 45 (1912), 3483) and

condensation of 2-methylbenzimidazole with benzaldehyde to the styryl compound and subsequent oxidation with KMnO₄ (S. Roseman, J. Amer. Chem. Soc. 75 (1953), 3854).

DE-A-1,033,667 discloses the reaction of imidazole with CO₂ under superatmospheric pressure, which gives imidazole-4(5)-carboxylic acid or imidazole-4,5-di-carboxylic acid. EP-A-172,407 discloses the analogous reaction with imidazole compounds which are unsubstituted in the 4- and 5-positions and various imidazole compounds which are monosubstituted in the 4(5)-position. Here the carboxyl group enters the imidazole ring in all cases only in position 4 (or 5).

Besides the imidazoles known from the aforementioned documents, 4,5-dichloro- and 4,5-dibromo-imidazole-2-carboxylic acid are known from DE-A-2,610,527, DE-A-2,634,053, Tetrahedron Letters 27 (1986), 1635-1638, and J. Heterocycl. Chem. 17 (1980), 409-411.

It is an object of the present invention to find a new and better way of obtaining 4,5-disubstituted imidazole-2-carboxylic acids.

We have found that this object is achieved with a novel process for preparing a 4,5-disubstituted imidazole-2-carboxylic acid, which comprises reacting a 4,5-disubstituted imidazole with carbon dioxide under superatmospheric pressure at from 150° to 300° C. in the presence of a base.

4,5-Disubstituted imidazole-2-carboxylic acids are obtainable by the following method:

The reaction takes place between a 4,5-disubstituted imidazole and carbon dioxide under superatmospheric pressure at from 150° to 300° C. in the presence of a base in accordance with the following reaction equation: ##STR1## The reactions are preferably carried out at from 150° to 300° C., particularly preferably at from 180° to 280° C., and under pressures of from 10 to 300 bar, preferably of from 10 to 180 bar, particularly preferably at from 40 to 180 bar.

The process may be carried out continuously or batchwise.

In general, the reaction is carried out under superatmospheric pressure and in the absence of a solvent.

4,5-Disubstituted imidazoles are mostly known and may be prepared by the methods described in K. Hofmann, Imidazole and its Derivatives, Interscience, New York 1953, p. 33 ff.

The molar ratio of carbon dioxide : 4,5-disubstituted imidazole is from 1:1 to 100:1, preferably from 1:1 to 10:1.

The carbon dioxide may be used for example in gaseous, liquid or solid form. Liquid carbon dioxide is preferred.

However, the reaction may also be carried out in the presence of a solvent or diluent.

Suitable solvents or diluents are for example aliphatic hydrocarbons such as n-pentane, n-hexane, mixed hexane isomers and petroleum ether, halogenated hydrocarbons such as chlorobenzene, methylene chloride, ethylene chloride, chloroform and tetrachloroethylene, aromatic hydrocarbons such as benzene, toluene, the xylenes and mixed isomers thereof, and naphtha, ethers such as diethyl ether, di-n-butyl ether, methyl tert.-butyl ether, tetrahydrofuran and dioxane, and aprotic dipolar solvents such as dimethylformamide, N-methylpyrrolidone or tetramethylurea. It is also possible to use mixtures of these substances as solvents/diluents.

The reaction time is normally from 1 to 20 hours, usually from 2 to 12 hours.

The product can be isolated in a conventional manner. To this end, the crude product is added to water, the solution is brought to pH 2-6 with inorganic acids at from 10° to 60° C. The precipitated product can subsequently be isolated by filtration. The inorganic acids used are preferably hydrochloric acid, sulfuric acid or phosphoric acid.

The substituents R¹ and R² and the indices n and m in the formula I independently of one another preferably have the following meanings for the process:

R¹ and R²

unbranched or branched C₁ -C₂₀ -alkyl, preferably unbranched or branched C₁ -C₁₂ -alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl, tert.-butyl, n-pentyl, iso-pentyl, sec.-pentyl, tert.-pentyl, neo-pentyl, 1,2-dimethylpropyl, n-hexyl, iso-hexyl, sec.-hexyl, n-heptyl, iso-heptyl, n-octyl, iso-octyl, n-nonyl, iso-nonyl, n-decyl, iso-decyl, n-undecyl, iso-undecyl, n-dodecyl and iso-dodecyl,

unbranched or branched C₂ -C₂₀ -alkoxyalkyl, preferably unbranched or branched C₂ -C₈ -alkoxyalkyl, such as methoxymethyl, ethoxymethyl, n-propoxymethyl, iso-propoxymethyl, n-butoxymethyl, iso-butoxymethyl, sec.-butoxymethyl, tert.-butoxymethyl, n-pentoxymethyl, iso-pent-oxymethyl, sec.-pentoxymethyl, tert.-pentoxymethyl, neo-pentoxymethyl, 1,2-dimethylpropoxymethyl, n-hexoxymethyl, iso-hexoxymethyl, sec.-hexoxymethyl, n-heptoxymethyl, iso-heptoxymethyl, methoxy-1-ethyl, ethoxy-1-ethyl, n-propoxy-1-ethyl, iso-propoxy-1-ethyl, n-butoxy-1-ethyl, iso-butoxy-1-ethyl, sec.-butoxy-1-ethyl, tert.-butoxy-1-ethyl, n-pentoxy1-ethyl, iso-pentoxy-1-ethyl, sec.-pentoxy-1-ethyl, tert.-pentoxy-1-ethyl, neopentoxy-1-ethyl, 1,2-dimethylpropoxy-1-ethyl, n-hexoxy-1-ethyl, iso-hexoxy-1-ethyl, sec.-hexoxy-1-ethyl, methoxy-2-ethyl, ethoxy-2-ethyl, n-propoxy-2-ethyl, iso-propoxy-2-ethyl, n-butoxy-2-ethyl, iso-butoxy-2-ethyl, sec.-butoxy-2-ethyl, tert.-butoxy-2-ethyl, n-pentoxy-2-ethyl, iso-pentoxy-2-ethyl, sec.-pentoxy-2-ethyl, tert.-pentoxy-2-ethyl, neo-pentoxy-2-ethyl, 1,2-dimethyl-propoxy-2-ethyl, n-hexoxy-2-ethyl, iso-hexoxy-2-ethyl and sec.-hexoxy-2-ethyl,

C₃ -C₁₂ -cycloalkyl, preferably C₃ -C₈ -cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl,

halogen, such as fluorine, chlorine, bromine and iodine, preferably chlorine and bromine,

arly phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-antrhyl and 9-anthryl particularly preferably phenyl,

C₇ -C₂₀ -alkylaryl, preferably C₇ -C₁₀ -alkylphenyl, such as 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethyl-phenyl, 3-ethylphenyl, 4-ethylphenyl, 2-n-propylphenyl, 3-n-propylphenyl, 4-n-propylphenyl, 2-iso-propylphenyl, 3-iso-propylphenyl, 4-iso-propylphenyl, 2-n-butylphenyl, 3-n-butylphenyl, 4-n-butylphenyl, 2-iso-butylphenyl, 3-iso-butylphenyl, 4-iso-butylphenyl, 2-sec.-butylphenyl, 3-sec.-butylphenyl, 4-sec.-butylphenyl, 2-tert.-butylphenyl, 3-tert.-butylphenyl and 4-tert.-butylphenyl,

C₇ -C₂₀ -alkoxyaryl, preferably C₇ -C₁₀ -alkoxyphenyl, such as 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-n-propoxyphenyl, 3-n-propoxyphenyl, 4-n-propoxyphenyl, 2-iso-propoxyphenyl, 3-iso-propoxyphenyl, 4-iso-propoxyphenyl, 2-n-butoxyphenyl, 3-n-butoxyphenyl, 4-n-butoxyphenyl, 2-iso-butoxyphenyl, 3-iso-butoxyphenyl, 4-iso-butoxyphenyl, 2-sec.-butoxyphenyl, 3-sec.-butoxyphenyl, 4-sec.-butoxyphenyl, 2-tert.-butoxyphenyl, 3-tert.-butoxyphenyl and 4-tert.-butoxyphenyl,

aryl which is disubstituted to trisubstituted by C₁ -C₈ -alkyl, preferably phenyl which is disubstituted or trisubstituted by C₁ -C₄ -alkyl, such as 2,4-dimethylphenyl, 3,4-dimethylphenyl and 3,4,5-trimethylphenyl,

aryl which is disubstituted or trisubstituted by C₁ -C₈ -alkoxy, preferably phenyl which is disubstituted or trisubstituted by C₁ -C₄ -alkoxy, such as 3,4-dimethoxyphenyl and 3,4,5-trimethoxyphenyl,

aryl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₄ -haloalkyl, preferably phenyl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₂ -fluoro- or -chloro-alkyl, particularly preferably phenyl which is monosubstituted, disubstituted or trisubstituted by trifluoromethyl or trichloroethyl, such as 4-trifluoromethylphenyl and 4-trichloromethylphenyl,

aryl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₄ -haloalkoxy, preferably phenyl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₂ -fluoro- or -chloroalkoxy, particularly preferably phenyl which is monosubstituted, disubstituted or trisubstituted by trifluoromethoxy or trichloromethoxy, such as trifluoromethoxyphenyl,

aryl which is monosubstituted, disubstituted or trisubstituted by halogen, preferably phenyl which is monosubstituted, disubstituted or trisubstituted by fluorine or chlorine, such as 4-chlorophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 4-fluorophenyl and 4-fluoro-3-chlorophenyl,

C₇ -C₂₀ -arylalkyl, preferably C₇ -C₁₀ -phenylalkyl, such as benzyl, phenethyl, 1-phenyl-n-propyl, 2-phenyl-n-propyl, 3-phenyl-n-propyl, 1-phenyl-iso-propyl, 2-phenyl-iso-propyl, 1-phenyl-n-butyl, 2-phenyl-n-butyl, 3-phenyl-n-butyl, 4-phenyl-n-butyl, 1-phenyl-iso-butyl, 2-phenyl-iso-butyl, 3-phenyl-iso-butyl, 1-phenyl-sec.-butyl, 1-benzyl-n-propyl, 2-phenyl-sec.-butyl, 3-phenyl-sec.-butyl and 1,1-dimethylphenethyl,

C₇ -C₂₀ -arylalkyl which is monosubstituted, disubstituted or trisubstituted by halogen in the aryl moiety, preferably C₇ -C₁₀ -phenylalkyl which is monosubstituted, disubstituted or trisubstituted by fluorine or chlorine in the phenyl moiety, such as 4-fluorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl and 3,4-dichlorobenzyl,

C₇ -C₂₀ -arylalkyl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₈ -alkyl in the aryl moiety, preferably C₇ -C₁₀ -phenylalkyl which substituted, disubstituted or trisubstituted by C₁ -C₄ -alkyl in the phenyl moiety, particularly preferably C₇ -C₁₀ -phenylalkyl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₂ -alkyl in the phenyl moiety, such as 4-methylphenyl, 4-ethylbenzyl and 4-methylphenethyl,

C₇ -C₂₀ -arylalkyl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₈ -alkoxy in the aryl moiety, preferably C₇ -C₁₀ -phenylalkyl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₄ -alkoxy in the phenyl moiety, particularly preferably C₇ -C₁₀ -phenylalkyl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₂ -alkoxy in the phenyl moiety, such as 4-methoxybenzyl, 4-ethoxybenzyl and 4-methoxyphenethyl,

C₇ -C₂₀ -arylalkyl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₄ -haloalkyl in the aryl moiety, preferably C₇ -C₁₀ -phenylalkyl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₂ -fluoro- or -chloroalkyl in the phenyl moiety, particularly preferably C₇ -C₁₀ -phenylalkyl which is monosubstituted, disubstituted or trisubstituted by trifluoromethyl or trichloromethyl in the phenyl moiety, such as 4-trifluoromethylbenzyl and 4-trichloromethylbenzyl,

C₇ -C₂₀ -arylalkyl which is monosubstituted, disubstituted or trisubstituted by C₁ -C₄ haloalkoxy in the aryl moiety, preferably C₇ -C₁₀ -phenylalkyl which is monosubstituted-, disubstituted or trisubstituted by C₁ -C₂ -haloalkyl in the phenyl moiety, particularly preferably C₇ -C₁₀ -phenylalkyl which is monosubstituted, disubstituted or trisubstituted by trifluoromethyl or trichloromethyl in the phenyl moiety, such as 4-trifluoromethoxybenzyl and 4-trichloromethoxybenzyl,

phenyl which is substituted by one, two or three phenoxy groups,

phenyl which is disubstituted or trisubstituted by halogen and C₁ -C₄ -alkyl, such as 2-methyl-4-chlorophenyl and 3-methyl-4-fluorophenyl,

phenyl which is disubstituted or trisubstituted by halogen and C₁ -C₄ -alkoxy, such as 3-chloro-4-methoxyphenyl,

phenyl which is disubstituted or trisubstituted by halogen and C₁ -C₄ -haloalkyl, such as 2-chloro-4-trifluoromethylphenyl

phenyl which is disubstituted or trisubstituted by halogen and phenoxy, such as 3-chloro-4-phenoxyphenyl,

phenyl which is disubstituted or trisubstituted by C₁ -C₄ -alkyl and C₁ -C₄ -alkoxy, such as 2-methyl-4-methoxyphenyl,

phenyl which is disubstituted or trisubstituted by C₁ -C₄ -alkyl and C₁ -C₄ -haloalkyl, such as 3-methyl-4-trichloromethylphenyl,

phenyl which is disubstituted or trisubstituted by C₁ -C₄ -alkyl and phenoxy, such as 2-methyl-4-phenoxyphenyl,

phenyl which is disubstituted or trisubstituted by C₁ -C₄ --alkoxy and C₁ -C₄ -haloalkyl, such as 3-trifluoromethyl-4-methoxyphenyl,

phenyl which is disubstituted or trisubstituted by C₁ -C₄ -alkoxy and phenoxy, such as 3-methoxy-4-phenoxyphenyl,

phenyl which is disubstituted or trisubstituted by C₁ -C₄ -haloalkyl and phenoxy, such as 3-trifluoromethyl-4-phenoxyphenyl,

phenyl which is trisubstituted by halogen, C₁ -C₄ -alkyl and C₁ -C₄ -alkoxy,

phenyl which is trisubstituted by halogen, C₁ -C₄ -alkyl and C₁ -C₄ -haloalkyl,

phenyl which is trisubstituted by halogen, C₁ -C₄ -alkyl and phenoxy, phenyl which is trisubstituted by halogen,

C₁ -C₄ -alkoxy and C₁ -C₄ -haloalkyl, phenyl which is trisubstituted by halogen, C₁ -C₄ -alkoxy and phenoxy,

phenyl which is trisubstituted by halogen, C₁ -C₄ -haloalkyl and phenoxy,

phenyl which is trisubstituted by C₁ -C₄ -alkyl, alkyl, C₁ -C₄ -alkoxy and C₁ -C₄ -haloalkyl,

phenyl which is trisubstituted by C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy and phenoxy,

phenyl which is trisubstituted by C₁ -C₄ -alkyl, C₁ -C₄ -haloalkyl and phenoxy,

phenyl which is trisubstituted by C₁ -C₄ -alkoxy, C₁ -C₄ -haloalkyl and phenoxy, R¹ and R² together

(CH₂)_(n), such as CH₂, (CH₂)₂, (CH₂)₃, (CH₂)₄, (CH₂)₅ and (CH₂)₆, preferably (CH₂)₃, (CH₂)₄, (CH₂)₅, (CH₂)₆, particularly preferably (CH₂)₃ and (CH₂)₄, (CH=CH)_(m), such as (CH=CH), (CH=CH)₂, (CH=CH)₃, preferably (CH=CH)₂, (CH=CH)₃ particularly preferably (CH=CH)₂,

n - from 1 to 6, preferably from 3 to 6, particularly preferably 3 and 4,

m - from 1 to 3, preferably 2 and 3, particularly preferably 2.

Of the substances themselves, those compounds are excluded from the listed meanings for the process where R¹ and R² are each halogen and where R¹ and R² are together (CH=CH)_(m).

The imidazole-2-carboxylic acids obtained are intermediates, for example for preparing drugs or dyes (DE-A-3,428,493).

PREPARATION EXAMPLES EXAMPLE 1 4,5-Dichloroimidazole-2-carboxylic acid (Compound No. 1)

A mixture of 137 g (1 mol) of 4,5-dichloroimidazole, 414 g (3 mol) of K₂ CO₃ and 1,000 ml of carbon dioxide was stirred in an autoclave at 200° C. under autogenous pressure for 10 hours. The solid output was pulverized, suspended in 2 1 of water and brought to pH 3-4 with concentrated hydrochloric acid while being cooled with ice. The resulting precipitate was filtered off and recrystallized from water to give 136 g (75%) of 4,5-dichloroimidazole-2-carboxylic acid (Compound No. 1); mp. 240° C. (dec.).

The method of Example 1 was also used to prepare the following compounds:

                                      TABLE 1                                      __________________________________________________________________________                  No. of                                                            Com-         moles of                                                                            No. of                                                                              Reaction                                                pound                                                                              Starting starting                                                                            moles of                                                                            tempera-                                                No. material material                                                                            K.sub.2 CO.sub.3                                                                    ture Product       mp.    Yield                         __________________________________________________________________________          ##STR2##                                                                               1    3    180° C.                                                                       ##STR3##     190° C.                                                                        68%.                          3                                                                                   ##STR4##                                                                               1    2    200° C.                                                                       ##STR5##     270° C.                                                                        66%.                          __________________________________________________________________________

EXAMPLE 2 Benzimidazole-2-carboxylic acid (Compound No. 4)

A mixture of 118 g (1 mol) of benzimidazole, g (2 mol) of K2CO3 and 400 ml of liquid carbon dioxide was stirred in an autoclave at 250° C. under autogenous pressure for 10 hours. The solid output was pulverized, suspended in 2.5 L of water and brought to pH 3-4 with concentrated hydrochloric acid while being cooled with ice. The resulting precipitate was filtered off and recrystallized from water to give 118 g (73%) of benzimidazole-2-carboxylic acid (Compound No. 4); mp. 170° C. (dec.).

The method of Example 2 was used to prepare the following compounds:

                                      TABLE 2                                      __________________________________________________________________________                       No. of                                                       Com-              moles of                                                                            No. of                                                                              Reaction                                           pound                                                                              Starting      starting                                                                            moles of                                                                            tempera-                                           No. material      material                                                                            K.sub.2 CO.sub.3                                                                    ture Product           mp.    Yield                __________________________________________________________________________          ##STR6##     1    2    250° C.                                                                       ##STR7##         155° C.                                                                        55%.                 6                                                                                   ##STR8##     1    2    250° C.                                                                       ##STR9##         140° C.                                                                        50%.                 __________________________________________________________________________ 

We claim:
 1. A process for preparing a 4,5-disubstituted imidazole-2-carboxylic acid, which comprises reacting a 4,5-disubstituted imidazole with carbon dioxide under superatmospheric pressure at from 150° to 300° C. in the presence of a base.
 2. The process for preparing a 4,5-disubstituted imidazole-2-carboxylic acid of the formula I ##STR10## where the substituents R¹ and R² are each independently of C₁ -C₂₀ -alkyl, C₂ -C₂₀ -alkoxyalkyl, C₃ -C₁₂ -cycloalkyl, halogen or unsubstituted or C₁ -C₈ -alkyl-, C₁ -C₈ -alkoxy-, halogen-, C₁ -C₄ -haloalkyl-, C₁ -C₄ -haloalkoxy- or phenoxy-substituted aryl or C₇ -C₂₀ -arylalkyl or are together unsubstituted or C₁ -C₈ -alkyl-, C₁ -C₈ -alkoxy- and/or halogen-monosubstituted or -disubstituted (CH₂)n or (CH═CH)_(m), where n is from 1 to 6 and m is from 1 to 3,by reacting a 4,5-disubstituted imidazole with carbon dioxide as in claim
 1. 3. The process for preparing a 4,5-disubstituted imidazole-2-carboxylic acid of claim 1, wherein the reaction is carried out in the presence of an inorganic carbonate, bicarbonate and/or hydroxide.
 4. The process for preparing a 4,5-disubstituted imidazole-2-carboxylic acid of in claim 1, wherein the reaction is carried out in the presence of an alkali metal bicarbonate, alkali metal or alkaline earth metal carbonate and/or alkali metal or alkaline earth metal hydroxide.
 5. The process for preparing an imidazole-2-carboxylic acid I of claim 1, wherein the reaction is carried out under a pressure of from 10 to 300 bar in the presence of an alkali metal carbonate, bicarbonate and/or hydroxide.
 6. The process for preparing an imidazole-2-carboxylic acid I of claim 1, wherein the reaction is carried out under a pressure of from 40 to 180 bar at from 180° to 280° C. in the presence of from 1 to 5 mol % of an alkali metal carbonate, bicarbonate and/or hydroxide.
 7. The process for preparing an imidazole-2-carboxylic acid I of claim 1, wherein the reaction is carried out under a pressure of from 40 to 180 bar at from 180° to 280° C. in the presence of from 1 to 3.5 mol % of potassium carbonate. 